Prior art processes for the production of 1,2-epoxy-3-amino-4-phenylbutane derivatives (1) (hereinafter also referred to as "epoxides (1)"), in particular (2S,3S)-1,2-epoxy-3-amino-4-phenylbutane derivatives (1a) (hereinafter also referred to as "epoxides (1a)"), which comprise subjecting (2S,3S)1-halo-2-hydroxy-3-amino-4-phenylbutane derivatives (hereinafter also referred to as "halohydrins (2a)") of the formula (2a) ##STR3## (wherein X is a halogen atom and P is as defined above), to ring closure under basic or alkaline conditions, are described, for example, in WO 96/17821, Japanese Kokai Publication Hei-08-109131, Japanese Kokai Publication Sho-62-126158 and Journal of Organic Chemistry, volume 59, pages 3656 ff (1994).
According to WO 96/17821, for instance, (2S,3S)-1-chloro2-hydroxy-3-N-(tert-butoxycarbonyl)amino-4-phenylbutane is converted to (2S,3S)-1,2-epoxy-3-N-(tert-butoxycarbonyl) amino-4-phenylbutane by treatment in THF (tetrahydrofuran) with a solution of KOH in methanol. The reaction mixture is poured into water, whereby (2S,3S)-1,2-epoxy-3-N-(tert-butoxycarbonyl)amino-4-phenylbutane is recovered as crystals (yield 96%, purity 90%).
According to Japanese Kokai Publication Hei-08-109131, (2S,3S)-1,2-epoxy-3-N-(tert-butoxycarbonyl)amino-4-phenylbutane is synthesized by adding a solution of KOH in ethanol to a suspension of (2S,3S)-1-chloro-2-hydroxy-3-N-(tert-butoxycarbonyl)amino-4-phenylbutane in ethanol, followed by 1 hour of stirring at room temperature. Thereafter, the ethanol is distilled off from the reaction mixture under reduced pressure, the residue is partitioned between ethyl acetate and water. The organic layer is washed with an aqueous solution of ammonium chloride, water and an aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated. The solid obtained is dissolved in ethyl acetate, hexane is then added and the mixture is cooled to -40.degree. C. By this recrystallization procedure, (2S,3S)-1,2-epoxy-3-N-(tert-butoxycarbonyl)amino-4-phenylbutane is isolated as crystals (yield 84%, purity 99.1%).
According to Japanese Kokai Publication Sho-62-126158, (2S,3S)-1,2-epoxy-3-N-(tert-butoxycarbonyl)amino-4-phenylbutane is synthesized by adding sodium hydride to a solution of (2S,3S)-1-chloro-2-hydroxy-3-N-(tert-butoxycarbonyl)amino-4-phenylbutane in THF, followed by overnight stirring. Thereafter, the reaction mixture is filtered, the filtrate is concentrated, the oily concentrate is dissolved in ethyl acetate, and the organic layer is washed in sequence with water, aqueous sodium hydrogen carbonate and aqueous potassium hydrogen sulfate, dried over sodium sulfate and then concentrated. The solid obtained is purified by column chromatography to give (2S,3S)-1,2-epoxy-3-N-(tert-butoxycarbonyl)amino-4-phenylbutane in 68% yield.
According to Journal of Organic Chemistry, volume 59, pages 3656 ff (1994), (2S,3S)-1,2-epoxy-3-N-(tert-butoxycarbonyl)amino-4-phenylbutane is synthesized by adding a solution of potassium hydroxide in methanol to a suspension of (2S,3S)1-bromo-2-hydroxy-3-N-(tert-butoxycarbonyl)amino-4-phenylbutane in methanol, followed by 3 hours of stirring at room temperature. Thereafter, the ethanol is distilled off from the reaction mixture, and the residue is partitioned between methylene chloride and water. The organic phase is dried over sodium sulfate and, after removal of the sodium sulfate, concentrated to dryness (yield 100%). The solid obtained is recrystallized from hexane to give analytically pure (2S,3S)-1,2-epoxy-3-N-(tert-butoxycarbonyl)amino-4-phenylbutane.
The starting halohydrins (2a), such as (2S,3S)-1-chloro2-hydroxy-3-N-(tert-butoxycarbonyl)amino-4-phenylbutane and (2S,3S)-1-bromo-2-hydroxy-3-N-(tert-butoxycarbonyl)amino-4-phenylbutan e can be prepared in a crystalline or solution form by the methods described in WO 96/23756, WO 96/17821, Japanese Kokai Publication Hei-08-109131, Japanese Kokai Publication Sho-62-126158 and Journal of Organic Chemistry, volume 59, pages 3656 ff (1994), for instance. According to said methods, the halohydrins (2a) are invariably synthesized starting with the corresponding L-phenylalanine derivatives.
(2R,3R)-1,2-Epoxy-3-amino-4-phenylbutane derivatives (hereinafter also referred to as "epoxides (1b)") of the formula (1b) ##STR4## (wherein P is as defined above), which are enantiomers to epoxides (1a), can be synthesized by quite the same methods as those described in the above-cited references via the corresponding (2R,3R)1-halo-2-hydroxy-3-amino-4-phenylbutane derivatives (hereinafter also referred to as "halohydrins (2b)") of the formula (2b) ##STR5## (wherein X and P are as defined above), starting with the corresponding D-phenylalanine derivatives, which are enantiomers to the L-phenylalanine derivatives.
Although the description which follows is limited to epoxides (1a), the same applies to epoxides (1b), which are enantiomers to (1a), provided that enanthiomers to those compounds with specified configurations which are mentioned in the following description are used.
The epoxides (1a) obtained in the above manner have a problem in that they tend to contain various impurities resulting from various decomposition and side reactions in the production process steps. In addition, the epoxides (1a) may be contaminated by some or other impurity contained in the starting halohydrins (2a) and/or a conversion product derived therefrom under the reaction conditions. Particular mention should be made of three kinds of impurity among most possibly coexisting impurities. In the following, the three impurities are described one by one (see the schematic illustration shown below). ##STR6##
The first kind of impurity comprises threo-(2R,3R)-1,2-epoxy-3-amino-4-phenylbutane derivatives (hereinafter also referred to as "threo-epoxides (3a)") of the formula (3a) ##STR7## (wherein P is as defined above). The threo-epoxides (3a) occurring as impurities in the epoxides (1a) are produced by cyclization of threo-1-halo-2-hydroxy-3-amino-4-phenylbutane derivatives (hereinafter also referred to as "threo-halohydrins (6a)") of the formula (6a) ##STR8## (wherein X and P are as defined above and the configurations at positions 2 and 3 are collectively 2R,3S), which occur in the starting halohydrins (2a), under the reaction conditions employed for the cyclization of halohydrins (2a).
The occurrence of threo-halohydrins (6a) in halohydrins (2a) results from the selectivity of the reaction determining the configurations at positions 2 and 3 in the synthesis of halohydrins (2a). Therefore, unless the synthesis of halohydrins (2a) proceeds with 100% selectivity or unless the byproducts threo-halohydrins (6a) are completely removed, the formation of threo-epoxides (3a) as byproducts cannot be avoided. No reactions are known to proceed with 100% selectivity, however. Thus, generally, it is very difficult to obtain halohydrins (2a) free of threo-halohydrins (6a). Purification by column chromatography or repetition of effective crystallization or recrystallization is indispensable and the employment of such procedures unfavorable to commercial scale production is unavoidable. Namely, the prior art technologies teaching the processes for producing halohydrins (2a) wO 96/23756; WO 96/17821; Japanese Kokai Publication Hei-08-109131; Japanese Kokai Publication Sho-62-126158; Journal of Organic Chemistry, volume 59, pages 3656 ff (1994)! each generally allows contamination of the starting halohydrins (2a) with the impurities threo-halohydrins (6a) unless such troublesome purification methods as mentioned above are used. When such contaminated halohydrins (2a) are used, the prior art technologies mentioned hereinabove (WO 96/17821; Japanese Kokai Publication Hei-08-109131; Japanese Kokai Publication Sho-626-126158) invariably and inevitably make it necessary to remove the threo-epoxides (3a).
As the second kind of impurity, there may be mentioned (2S,3S)1-alkoxy-2-hydroxy-3-amino-4-phenylbutane derivatives (hereinafter also referred to as "epoxy ring opening products (4a)") of the formula (4a) ##STR9## (wherein P is as defined above and A is an alkoxy group). In carrying out the cyclization of halohydrins (2a) to epoxides (1a), an alcoholic alkali metal hydroxide or an alkali metal alkoxide is used as a base in most cases. An investigation made by the present inventors revealed that when such base is used for the cyclization reaction of halohydrins (2a) to epoxides (1a), the epoxides (1a) formed are decomposed by the alcohol or alkoxide occurring in the reaction system and the epoxy ring opening products (4a) as byproducts are formed in considerable amounts. This formation of epoxy ring opening products (4a) as byproducts is the main cause of decreased yields. In particular, it was found that when the epoxides (1a) are synthesized by the processes of WO 96/17821, Japanese Kokai Publication Hei-08-109131 and Journal of Organic Chemistry, volume 59, pp. 3656 ff (1994), it is very difficult to suppress the formation of epoxy ring opening products (4a) as byproducts, the reaction can never proceed quantitatively and therefore it is very important to remove them for the purification of (1a).
As the third kind of impurity, there may be mentioned (3S)-2-hydroxy-3-amino-4-phenylbutane derivatives (hereinafter also referred to as "dehalogenation products (5a)") of the formula (5a) ##STR10## (wherein P is as defined above).
The dehalogenation products (5a) are compounds with a structure such that the halogen atom in halohydrins (2a) has been replaced by a hydrogen atom. Why said dehalogenation products (5a) are formed as byproducts is not clear. An investigation by the present inventors, however, revealed that the dehalogenation products (5a) originally occurring in the starting halohydrins (2a) remain unchanged under the cyclization reaction conditions and are brought, as they are and as impurities, into the epoxides (1a). An investigation by the present inventors further revealed that, among the prior art technologies for the production of halohydrins (2a), at least the technology of WO 96/23756 allows the formation of said dehalogenation products.
To sum up, the formation of such various impurities such as threo-epoxides (3a), epoxy ring opening products (4a) and dehalogenation products (5a) and the difficulty of removing them are the major causes of the difficulty in producing high-quality epoxides (1a). As is generally known in the art, related impurities, namely impurities similar in structure to desired products, are difficult to remove for purifying said desired products. For obtaining high-quality desired products, a production process involving a reaction scheme by which byproduct formation can be prevented as far as possible as well as a purification method enabling a high level elimination of impurities is required.
The prior art processes have not only the above-mentioned problems from the quality viewpoint but also other various problems from the method of obtaining viewpoint, for example from the viewpoint of workability or productivity.
Thus, for example, the process of WO 96/17821 is a recipe involving the formation of epoxy ring opening products (4a) as byproducts; it is difficult to obtain high-quality epoxides (1a) and only low purity crystals with at most 90% purity can be obtained. As a result of an investigation by the present inventors, it was found that said process additionally has productivity problems; for example the separation of crystals by filtration is not easy.
The process of Japanese Kokai Publication Hei-08-109131 is also a recipe according to which the formation of epoxy ring opening products (4a) as byproducts is very difficult to suppress, Said process has many problems as regards the method of product recovery as well. For example, two concentration procedures are required, an undesirable organic solvent is used in large amounts, and a cryostat is required to maintain a temperature of -40.degree. C. For these and other reasons, said process is a troublesome, expensive and time-consuming one. Furthermore, the yield is around 84%, hence quite unsatisfactory.
The process of Japanese Kokai Publication Sho-62-126158, too, has too many drawbacks to be put to practical use on a commercial scale; for example, sodium hydride, which is hazardous, is used, two concentration procedures are required, an undesirable organic solvent is used in large amounts, and purification by column chromatography is required. Furthermore, the yield is as low as 68%.
The process of Journal of Organic Chemistry (volume 59, pages 3656 ff, 1994) is also a process essentially involving the formation of epoxy ring opening products (4a) as byproducts and has too many drawbacks to be put to practical use on a commercial scale; for example, two concentration procedures are required, an undesirable organic solvent is used in large amounts, and recrystallization is required.
As mentioned above, the prior art processes each has various drawbacks in employing them in the production on a commercial scale, such as the use of an undesirable organic solvent in large amounts, the complicatedness of process steps, time consumption resulting therefrom, the increases in number and capacity of (expensive) production apparatus and the decreases in yield.
HIV protease inhibitors currently attracting much attention are drugs required to be taken at high doses and therefore it is desired that measures be taken to avoid adverse reactions due to trace impurities and achieve mass production at a cost as low as possible. In such circumstances, it is of particular significance to develop a process for producing high quality epoxides (1a), which are intermediates for the production of HIV protease inhibitors, on a commercial scale with high productivity.